Medical devices which serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters and the like in and on the body or as extracorporeal devices intended to be connected to the body to assist in surgery or dialysis are well known. However, the use of biomaterials in medical devices can stimulate adverse body responses, including rapid thrombogenic action. Various plasma proteins play a role in initiating platelet and fibrin deposition on biomaterial surfaces. These actions lead to vascular constriction that hinder blood flow, and the inflammatory reaction that follows can lead to the loss of function of the medical device. Biologically active entities that reduce or inhibit thrombus formation on the surface of a biomaterial and/or covering material are of particular interest for blood contacting devices. Glycosaminoglycans are generally preferred anti-thrombotic agents; with heparin, heparin analogs, and derivatives being particularly preferred.
Immobilization of glycosaminoglycans, such as heparin, to biomaterials has been researched extensively to improve bio- and hemocompatibility. The mechanism responsible for reducing thrombogenicity of a heparinzed material is believed to reside in the ability of heparin to speed up the inactivation of serine proteases (blood coagulation enzymes) by anti-thrombin III (ATIII). In the process, ATIII forms a complex with a well defined pentasaccharide sequence in heparin, undergoing a conformational change and thus enhancing the ability of ATIII to form a covalent bond with the active sites of serine proteases, such as thrombin. The formed serine protease-ATIII complex is then released from the heparin, leaving said heparin behind for subsequent rounds of inactivation via a catalytic process.
Immobilization of biologically active entities, such as heparin, on biomaterials in a biologically active form involves an appreciation of the respective chemistries of the entity and the biomaterial. In the field of medical devices, ceramic, polymeric, and/or metallic materials are common biomaterials. These materials can be used for implantable devices, diagnostic devices or extracorporeal devices. Modification of the chemical composition of a biomaterial is often required to immobilize a biologically active entity thereon. This modification is usually accomplished by treating surfaces of the biomaterial to generate a population of chemically reactive moieties or groups, followed by immobilization of the biologically active entity with an appropriate protocol. With other biomaterials, surfaces of a biomaterial are covered, or coated, with a material having reactive chemical groups incorporated therein. Biologically active entities are then immobilized on the biomaterial through the reactive chemical groups of the covering material. A variety of schemes for covering, or coating, biomaterials have been described. Representative examples of biologically active entities immobilized to a biomaterial with a covering, or coating, are described in U.S. Pat. Nos. 4,810,784; 5,213,898; 5,897,955; 5,914,182; 5,916,585; and 6,461,665.
When biologically active compounds, compositions, or entities are immobilized, the biological activity of these “biologics” can be negatively impacted by the process of immobilization. The biological activity of many biologics is dependent on the conformation and structure (i.e., primary, secondary, tertiary, etc.) of the biologic in its immobilized state. In addition to a carefully selected immobilization process, chemical alterations to the biologic may be required for the biologic to be incorporated into the covering material with a conformation and structure that renders the biologic sufficiently active to perform its intended function.
Despite an optimized covering and immobilization scheme, additional processing, such as sterilization, can degrade the biological activity of the immobilized biologic. For implantable medical devices, sterilization is required prior to use. Sterilization may also be required for in vitro diagnostic devices having sensitivity to contaminants. Sterilization of such devices often requires exposure of the devices to elevated temperature, pressure, and humidity, often for several cycles. In some instances, antimicrobial sterilants, such as ethylene oxide gas (EtO) or vapor hydrogen peroxide, are included in the sterilization process. In addition to sterilization, mechanical compaction and expansion, or long-term storage of an immobilized biologic can degrade the activity of the biologic.
There exists a need for medical devices having biologically active entities immobilized thereon that can be subjected to sterilization, mechanical compaction and expansion, and/or storage without significant loss of biological activity. Such a medical device would have biologically compatible compositions or compounds included with the immobilized biological entities that serve to minimize degradation of the biological activity of the entities during sterilization, mechanical compaction and expansion, and/or storage. In some instances, the additional biologically compatible compositions or compounds would increase the biological activity of some biologically active entities following a sterilization procedure.